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      Lactylation-related gene signature accurately predicts prognosis and immunotherapy response in gastric cancer

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          Abstract

          Background

          Gastric cancer (GC) is a malignant tumor associated with significant rates of morbidity and mortality. Hence, developing efficient predictive models and directing clinical interventions in GC is crucial. Lactylation of proteins is detected in gastric cancer tumors and is linked to the advancement of gastric cancer.

          Methods

          The The Cancer Genome Atlas (TCGA) was utilized to analyze the gene expression levels associated with lactylation. A genetic pattern linked to lactylation was created using Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. The predictive ability of the model was evaluated and confirmed in the Gene Expression Omnibus (GEO) cohort, where patients were divided into two risk groups based on their scores. The study examined the relationship between gene expression and the presence of immune cells in the context of immunotherapy treatment. In vitro cytotoxicity assays, ELISA and PD-1 and PD-L1interaction assays were used to assess the expression of PD-L1 while knocking down SLC16A7.

          Results

          29 predictive lactylation-related genes with differential expression were discovered. A signature consisting of three genes was developed and confirmed. Patients who had higher risk scores experienced worse clinical results. The group with lower risk showed increased Tumor Immune Dysfunction and Exclusion (TIDE) score and greater responsiveness to immunotherapy. The tumor tissues secrete more lactate acid than normal tissues and express more PD-L1 than normal tissues, that is, lactate acid promotes the immune evasion of tumor cells. In GC, the lactylation-related signature showed strong predictive accuracy. Utilizing both anti-lactylation and anti-PD-L1 may prove to be an effective approach for treating GC in clinical settings. We further proved that one of the lactate metabolism related genes, SCL16A7 could promote the expression of PD-L1 in GC cells.

          Conclusion

          The risk model not only provides a basis for better prognosis in GC patients, but also is a potential prognostic indicator to distinguish the molecular and immune characteristics, and the response from Immune checkpoint inhibitors (ICI) therapy and chemotherapy in GC.

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          Most cited references43

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              Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2199749Role:
                URI : https://loop.frontiersin.org/people/2828237Role:
                URI : https://loop.frontiersin.org/people/2432375Role: Role:
                URI : https://loop.frontiersin.org/people/2141330Role: Role:
                URI : https://loop.frontiersin.org/people/1653481Role: Role:
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                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                28 November 2024
                2024
                : 14
                : 1485580
                Affiliations
                [1] 1 Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University , Shenzhen, Guangdong, China
                [2] 2 Hospital for Skin Diseases, Shandong First Medical University , Jinan, Shandong, China
                Author notes

                Edited by: Wenle Li, Xiamen University, China

                Reviewed by: Yulou Luo, Xinjiang Medical University, China

                Songou Zhang, Ningbo University, China

                *Correspondence: Songcheng Yin, yinsch3@ 123456mail.sysu.edu.com ; Changhua Zhang, zhchangh@ 123456mail.sysu.edu.cn

                †These authors have contributed equally to this work and share first authorship

                Article
                10.3389/fonc.2024.1485580
                11634757
                39669362
                89cb6177-683e-4c1b-b968-2a1a06b7f550
                Copyright © 2024 Sun, Dong, Su, Chen, Li, Yin and Zhang

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 August 2024
                : 07 November 2024
                Page count
                Figures: 8, Tables: 1, Equations: 0, References: 43, Pages: 16, Words: 6700
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Guangdong Provincial Key Laboratory of Digestive Cancer Research (No. 2021B1212040006), Sanming Project of Medicine in Shenzhen (No. SZSM201911010) and Shenzhen Key Medical Discipline Construction Fund (No. SZXK016).
                Categories
                Oncology
                Original Research
                Custom metadata
                Gastrointestinal Cancers: Gastric and Esophageal Cancers

                Oncology & Radiotherapy
                gastric cancer,lactylation-related genes,prognostic signature,pd-l1,immunotherapy

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